title: ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss.
abstract: Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN-deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. cheny1@mskcc.org
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Chi
authors.forename: Shira
authors.initials: S
authors.lastname: Rockowitz
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Iaquinta
authors.forename: Tambudzai
authors.initials: T
authors.lastname: Shamu
authors.forename: Shipra
authors.initials: S
authors.lastname: Shukla
authors.forename: Dong
authors.initials: D
authors.lastname: Gao
authors.forename: Inna
authors.initials: I
authors.lastname: Sirota
authors.forename: Brett S
authors.initials: BS
authors.lastname: Carver
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005796:Genes / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008297:Male; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000378:metabolism; D010641:Phenotype; D025341:Principal Component Analysis; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D059467:Transcriptome / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C531115:ERG protein, mouse; C095239:ETV1 protein, human; D006657:Histones; D015513:Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011944:Receptors, Androgen; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D051059:PTEN Phosphohydrolase; D008239:Lysine